Brandon Foreman and Anil Mendiratta
BACKGROUND
Seizure is a common emergency department (ED) presentation. Seizing patients may arrive actively convulsing, with a depressed level of consciousness, or comatose. In these patients, the emergency physician's challenges are to provide immediate and appropriate treatment, to evaluate for ongoing seizures or status epilepticus (SE), and to assess for seizure cause. The adage “time is brain” is as relevant to the treatment of seizure as it is in stroke therapy; early identification and control of ongoing seizures minimizes neurologic injury, reduces complications, and improves patient outcomes.
EPIDEMIOLOGY
Based on a nationwide sample, seizures account for an estimated 1.1 million visits to US EDs each year.1 Just over 11% of the population will experience a seizure in the course of a lifetime, and approximately 1% of the population carries a diagnosis of epilepsy or recurrent unprovoked seizures.2,3 Worldwide, the age-adjusted incidence of unprovoked seizures is around 60/100,000 person-years.3,4Approximately one-third of these are first-time seizures occurring in patients who otherwise will not develop epilepsy. Acute symptomatic seizures (also called provoked seizures) result from a clear underlying acute cause such as trauma, stroke, or hypoglycemia and have an age-adjusted incidence between 20 and 40/100,000 person-years.4
The majority of patients evaluated in the ED for seizures arrive by ambulance5; one-quarter of these patients require advanced life support (ALS) management by paramedics.6 Over 25% of patients who present with seizures will be admitted to the hospital, and 1% will require endotracheal intubation for mechanical ventilation.1 Mortality varies based on etiology, and while seizure patients rarely die in the ED,1 the short-term 30-day mortality following an acute symptomatic seizure is reported to be as high as 19%.7
SE occurs when seizures are prolonged (>5 minutes) or recur before the patient fully recovers. Any patient who arrives to the ED seizing should be considered in SE. SE is diagnosed in up to 6% of all ED seizure presentations,5 and has been estimated to occur in up to 152,000 patients annually in the United States alone.8
Nonconvulsive seizures are those in which the patient has only subtle or no overt clinical signs of ongoing seizures (other than depressed level of consciousness), but electroencephalography (EEG) demonstrates ongoing electrographic seizure activity. Nonconvulsive SE is seen in nearly half of patients who remain comatose after apparent control of initial convulsive SE.9 While the incidence of nonconvulsive SE is reported to occur in one-quarter of all SE, this is likely an underestimate because continuous EEG monitoring is not immediately available in many medical centers.10
SE is associated with significant morbidity and mortality. Overall mortality is estimated to be 20%,8 and this number climbs substantially when SE is associated with an acute symptomatic cause, advanced age, concurrent medical illness, and/or prolonged time to achieve seizure control.11,12 Of these factors, only the duration of SE is modifiable, and it correlates with outcome: when SE resolves within 30 minutes, the reported mortality is 3%, compared to 19% with resolution after 30 minutes,13 and 32% with resolution after 60 minutes.11 Of those patients that survive SE, 41% will develop epilepsy.14
PREHOSPITAL EVALUATION AND MANAGEMENT
In the vast majority of cases, seizures will have resolved by the time paramedics arrive on the scene. Once in the ED, timely gathering of patient information—including a history of prior epilepsy or neurologic injury/disorder, an accurate medication list, and a point-of-care glucose—will facilitate appropriate care.
Patients in whom seizures have resolved may be safely transported to the ED by emergency medical services (EMS) for further evaluation without advanced life support (ALS) monitoring (i.e., a basic life support, or BLS unit).6 However, one-quarter of patients with a chief complaint of seizure will have evidence of a serious concurrent illness/injury or neurologic/cardiopulmonary instability, often due to ongoing seizures or SE.6 Given the delays associated with the resuscitation of the patient, transportation, and triage upon arrival,15 it is essential to initiate early and adequate treatment of seizures prior to arrival to the ED. In addition to providing basic support, evidence supports the prompt administration of benzodiazepines (e.g., lorazepam, midazolam, or diazepam) in the prehospital setting by ALS providers, as these agents have been shown to terminate seizures and SE more effectively than placebo16 or phenytoin alone.17 Adequate benzodiazepine dosing in the field also results in significantly fewer seizure-related complications including respiratory failure requiring intubation16 (Table 22.1).
TABLE 22.1 Prehospital Evaluation of Seizures or SE
ED, emergency department; EMS, emergency medical service; IM, intramuscular; IV, intravenous.
Because intravenous (IV) lorazepam requires IV access and must be refrigerated in order to maintain stability in solution, rectal diazepam—despite its inferiority in a prospective, population-based study—has long been used in the home and acute care settings for children or adults with epilepsy who experience recurrent seizures.18–20 In 2010, a meta-analysis of seizure control in children and young adults demonstrated intramuscular (IM), intranasal, or buccal midazolam also provides faster and more efficacious treatment when compared to diazepam by any route.21 In 2012, a randomized controlled trial of IM midazolam versus IV lorazepam (the RAMPART trial) demonstrated IM midazolam to be more rapidly administered and at least as effective as IV lorazepam in terminating seizures and SE in adults, making IM midazolam an ideal choice for EMS or ED providers.22 Evidence for the use of buccal and intranasal forms of midazolam in the adult population is lacking23,24 (Fig. 22.1).
FIGURE 22.1 A sample protocol for the comprehensive evaluation and management of seizures and status epilepticus. *Treatment dosing recommendations are for adult patients >40 kg. ALS, advanced life support; EEG, electroencephalography; ED, emergency department; EMS, emergency medical services; GCSE, generalized convulsive status epilepticus; ICU, intensive care unit; IM, intramuscular; IV, intravenous; LCS, lacosamide; LEV, levetiracetam; FosPHT/PHT, fosphenytoin/phenytoin; SE, status epilepticus; VPA, valproic acid.
EMERGENCY DEPARTMENT DIAGNOSTIC EVALUATION
Seizures and SE resolve in approximately 70% of patients who are promptly treated with adequately dosed benzodiazepines, either en route to or upon arrival to the ED.16,17,22,25 Once a patient demonstrates an improving level of consciousness, further treatment for the initial seizure may not be required. The emergency physician should continue the initial prehospital investigation into the cause of the seizures or SE and concurrently manage any recurrent seizures and associated illnesses (Table 22.2).
TABLE 22.2 ED Evaluation of Seizures or SE
AED, antiepileptic drug; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging.
Patients with History of Epilepsy
If the patient takes antiepileptic drugs (AEDs) and/or has a known history of epilepsy, a careful history and evaluation should assess for a reason that the patient's seizure threshold might be reduced (e.g., missed medications, excessive sleep deprivation or alcohol intake, concurrent illness). The patient's neurologist should be contacted for further information and recommendations. If the patient has fully recovered, a safe discharge plan often can be made in conjunction with the patient's outpatient neurologist. If there is a history of missed medication doses, the neurologist may advise a partial “loading” dose in the ED. If there is no history of noncompliance, an increase in the standing AED dose may be advised. A brief low-dose benzodiazepine taper, such as lorazepam 0.5 to 1 mg once or twice daily for 1 to 3 days, may also be recommended in order to minimize the risk of seizure recurrence over the next few days as AED dosage adjustments are made. It is important to ensure that while the patient is being observed in the ED, he or she is administered all of his/her regularly scheduled AED doses. Of note, some of the newer AEDs are nonformulary in many hospitals; AEDs cannot be substituted for one another (e.g., the patient who is taking lacosamide [LCS] should not be given phenytoin or carbamazepine because LCS is unavailable).
As emergency physicians often function as the default primary physician for many community patients, they should be alert for patients who repeatedly visit the ED for seizures. Patients with recurrent unprovoked seizures despite compliance with AEDs have refractory or pharmacoresistant epilepsy.26 Refractory epilepsy patients should be referred to a comprehensive epilepsy center, where optimal management of AEDs may improve seizure control; these patients may also be evaluated for potentially curative epilepsy surgery, which has been shown to be more effective than medication in many patients.27
Patients with a Resolved Seizure Episode
Patients who present after a first-time unprovoked seizure should have a complete ED evaluation as outlined in Table 22.2. Prompt imaging is important, as approximately 10% of patients with a first-time unprovoked seizure will be found to have abnormality on head CT or brain MRI that warrants further evaluation.28 If the patient has no risk factors for epilepsy (i.e., no history of neurologic injury, significant head trauma, CNS infection, or family history of epilepsy), and the neurologic examination and brain imaging (noncontrast head CT or brain MRI) are normal, an AED does not need to be started in the ED. These patients have a risk of seizure recurrence of approximately 40% over the next 2 years,29 and consequently, many opt to defer AED treatment until a second definite unprovoked seizure occurs. However, an outpatient EEG should be arranged, as approximately one-third will have an EEG with epileptiform discharges, effectively doubling the risk for seizure recurrence.28 Because of the risk of seizure recurrence, patients with a first-time unprovoked seizure should be advised against driving, and both patients and their families should be educated about seizure precautions and seizure first aid. An outpatient neurology consultation can help guide further diagnostic evaluation and discussions about prognosis with regard to risk of seizure recurrence, AEDs, and activity restrictions.
Importantly, the patient who has recovered to baseline following an isolated seizure does not require administration of IV/IM benzodiazepines, or the rapid IV loading dose of an AED, such as phenytoin. These may needlessly sedate the patient or cause unwarranted complications such as respiratory depression or hemodynamic instability.
Patients with acute symptomatic seizures (seizures provoked by systemic illness or brain injury, as opposed to seizures without a clear underlying cause) are typically admitted for evaluation and management of the underlying etiology (e.g., intracranial hemorrhage, CNS infection) uncovered during their evaluation, as well as for observation for seizure recurrence. Depending upon the cause of the seizure, treatment with an AED may be indicated in order to minimize the risk of recurrent seizures and their associated complications. Consultation with a neurologist is always warranted in these cases.
MANAGEMENT GUIDELINES
First-Time or Resolved Seizure
Patients with a first-time seizure found to be at risk for seizure recurrence based on diagnostic evaluation (e.g., abnormal neuroimaging or epileptiform abnormalities on EEG) warrant treatment initiation with an AED. Consultation with a neurologist is advisable in order to guide the selection of the AED. However, if a neurologist is not available, the emergency physician should consider both the adverse effects and drug–drug interactions of the AED that is chosen. Although phenytoin (PHT) has traditionally been considered a default AED, current consensus recommends against PHT as a first-line agent because of its relatively unfavorable adverse effect profile, pharmacokinetics, and prominent drug–drug interactions. Newer-generation AEDs, such as levetiracetam (LEV), may be more appropriate for several reasons: broad-spectrum action (e.g., effective for both partial and generalized-onset seizures), renal excretion, lack of hepatic induction, and absence of drug–drug interactions. Importantly, the emergency physician should also consider individual medical and psychiatric comorbidities. Patients should be educated on potential adverse medication effects, such as allergic reactions, and arrangements should be made for neurology follow-up evaluation within a few weeks.
Status Epilepticus
For the patients who arrive to the ED seizing, or those who develop recurrent, ongoing seizures while in the ED, rapid and aggressive treatment to stop seizures is critical. Current laboratory evidence suggests that within minutes, seizure activity produces changes in the synaptic membrane receptors, altering the balance between inhibitory and excitatory neurotransmission, followed by changes in neuropeptide expression. The excitotoxicity that results culminates in neuronal death, which may be widespread after prolonged (or self-sustaining) SE.30 Human data are limited, but seminal primate studies have clearly shown that even in the absence of the systemic effects of SE (e.g., hyperthermia, hypoxia), prolonged SE can cause ischemic neuronal loss, likely related to cerebral metabolic supply–demand mismatch.31 In humans, even very focal seizures visible only using intracranial electrodes but lasting longer than 5 minutes create clear changes in brain and systemic physiology,32 suggesting that seizures create a dangerous environment for sensitive neurons.
Response to medication can drop by as much as 50% when medications are either underdosed or given in a delayed manner such that SE is prolonged beyond 120 minutes.33,34 Reducing the time to initial adequate treatment is challenging, as EMS run times average between 20 and 40 minutes,6,16 and patients may experience subsequent delays to hospital triage and treatment of up to 50 minutes.15,25 If SE continues from the ambulance to the hospital, adherence to an established ED clinical protocol may be the most important factor in shortening the duration of SE, minimizing the likelihood of conversion to refractory SE, and reducing the intensive care unit (ICU) length of stay25 (Fig. 22.2).
FIGURE 22.2 A sample protocol for the ED management of generalized convulsive SE. ABCs, airway, breathing, and circulation; ABG, arterial blood gas; AEDs, antiepileptic drugs; BMP, basic metabolic panel; BP, blood pressure; Ca, calcium; CBC, complete blood count; cEEG, continuous electroencephalographic monitoring; ECG electrocardiogram; HR, heart rate; ICU, intensive care unit; LFTs, liver function tests; Mg, magnesium; PO4, phosphorous. Modified from Foreman B, Hirsch LJ. Epilepsy emergencies: diagnosis and management.Neurol Clin. 2012;30:11–41.
Unfortunately, studies to date have demonstrated poor adherence to established ED protocols, including both dosage and timing of medications.15,25,35 In one study, no patient received an adequate dose of phenytoin.16 In another, more than 50% of patients received initial treatment more than 1 hour after the onset of SE.35 The inclusion of both prehospital- and ED-based management as part of a unified treatment protocol for SE has not yet been studied adequately. A recently proposed Emergency Neurological Life Support protocol builds upon data showing improved outcomes with reduced treatment time in patients with acute myocardial infarction and highlights the importance of continuity in care from the ambulance to the hospital bed.36
Medical Therapy
For the patient in SE (i.e., arrived to the ED seizing or with recurrent ongoing seizure in the ED), IV benzodiazepines are the first line of treatment. If IV access is available, lorazepam 4 mg IV over 2 minutes should be administered immediately. If IV access cannot be obtained rapidly, midazolam 10 mg IM should instead be administered. Rectal diazepam 15 to 20 mg is an alternative if IM midazolam is not immediately available. If the patient continues to have clinical seizures, benzodiazepine dosing may be repeated; at this point, the patient will likely require airway support. If not already done in the prehospital setting, point-of-care glucose testing should be performed immediately. Low or borderline low serum glucose should be treated with thiamine 100 mg IV followed by 50 mL D50W (given together to prevent acute thiamine deficiency).
Second-Line Agents
All patients presenting with SE should be started on a second-line AED following the administration of initial benzodiazepines—even if seizure activity is terminated—in order to prevent seizure recurrence as the effect of the benzodiazepines wanes over the next several hours. For patients who continue to seize, or who do not regain consciousness despite adequate benzodiazepine dosing (in the field and/or in the ED), rapid initiation of a second-line agent is critical. If benzodiazepines were given in the prehospital setting, second-line agents should be initiated at the same time as the first-line ED benzodiazepine therapy.
Phenytoin (PHT) is the traditional second-line agent. PHT is frequently underdosed (the usual 1,000 mg IV load is only adequate for a 50-kg person)15; the appropriate dosing is 20 mg/kg at a rate of 50 mg/min. For this dose, cardiac monitoring is required; hypotension is a common side effect requiring slower infusion rates.17 Of note, PHT solvent extravasation from a peripheral IV can cause significant tissue injury. A rare idiosyncratic reaction causing digital ischemia, known as the “purple glove syndrome,” has also been reported with IV PHT.
Fosphenytoin, a water-soluble PHT prodrug, avoids these complications, is associated with fever hypotensive episodes, and may be infused more rapidly (up to 150 mg/min). However, fosphenytoin is substantially more expensive, costing nearly eight times as much as PHT.37 Cardiac arrhythmias and respiratory depression can occur with both medications. PHT is highly protein bound, induces the hepatic cytochrome P450 enzymatic system (specifically CYP3A and CYP2C), and may interact with other medications or AEDs. As such, PHT may cause problematic drug–drug interactions in patients with HIV, cancer, or solid organ transplants.
Valproic acid (VPA) has been studied in five randomized controlled trials recently included in a meta-analysis and appears to be at least as effective as PHT with fewer overall adverse effects.38 VPA loading doses range between 20 and 40 mg/kg over 10 minutes. Side effects include hyperammonemia and pancreatitis and an increased risk of bleeding due to diminished platelet activation, prolonged thrombin time, and dose-dependent thrombocytopenia.39,40 Importantly, cardiac arrhythmias and hypotension are rare, even among the elderly or critically ill.41 VPA is protein bound like PHT, but acts as an inhibitor of CYP2C9, increasing the bioavailability of medications such as warfarin, amitriptyline, and clopidogrel. For both PHT and VPA, free and total serum drug levels should be drawn for the initial monitoring of these medications given their protein binding and pharmacokinetics.
Other Second-Line Agents
LEV, LCS, and phenobarbital are three additional second-line agents that may be considered in special circumstances. Intravenous LEV is negligibly protein bound and does not interact with hepatically cleared medications. Loading doses of 1,000 to 3,000 mg infused over 15 minutes are associated with minimal side effects.42 However, studies of LEV as a second-line agent are lacking: Only one prospective study randomized patients to LEV either as a first-line or a second-line agent, and most were treated without benzodiazepines.43 In a prospective observational study comparing LEV to phenobarbital and VPA as second-line agents in the treatment of SE, LEV demonstrated a higher risk for treatment failure compared to VPA when controlled for the severity of SE and potentially fatal underlying causes (odds ratio 2.69).44 LCS is a relatively new IV agent with limited data available regarding efficacy. Like LEV, LCS has limited drug–drug interactions, and safety has been demonstrated with IV loading doses up to 400 mg over 15 minutes. Adverse effects include dizziness, nausea, and a dose-dependent prolongation of the PR interval on electrocardiography of unclear clinical significance.45 Because of the lack of drug interactions, LCS and LEV may be considered as options in patients being treated for HIV, cancer, or solid organ transplants, although studies regarding this are lacking. Phenobarbital, an early antiepileptic agent limited by adverse effects, is administered as a 20 mg/kg load at 50 mg/min (similar to phenobarbital). Although its use in SE was comparable to lorazepam in a randomized clinical trial,17 it requires a slow load time to avoid well-documented side effects including hypotension and respiratory depression. Airway support and possibly mechanical ventilation should be instituted prior to administration of an IV phenobarbital load. Phenobarbital should be considered only if other agents are unavailable, or if a patient on phenobarbital as an outpatient presents with subtherapeutic levels.
Refractory Status Epilepticus
SE usually stops after adequate dosages of first- and second-line medications. If not responsive to first- and second-line agents, SE is considered refractory.46,47 When SE has truly stopped, a postictal state frequently develops, characterized by alterations in consciousness or cognition, behavior, or motor function. The postictal state is related to the type and duration of seizures: After focal seizures lasting a mean of 128 seconds recorded on video-EEG, one study documented postictal periods consisting of confusion, aphasia, or subtle nonpurposeful movements that lasted on average for 89 seconds.48 In another study, following generalized convulsions captured on video, patients appeared unresponsive for up to 20 minutes (mean time of ~4 minutes) prior to first nonrespiratory movement.49 Therefore, if seizures have stopped and the patient has not begun to improve neurologically within 20 minutes, or has not returned to baseline by 60 minutes, nonconvulsive SE should be considered.
Aggressive treatment for refractory generalized convulsive SE should begin in the ED. Close cardiopulmonary monitoring and support is crucial to reduce the risk for complications and ensure safe transition to the ICU. Endotracheal intubation and mechanical ventilation is frequently required.46 Paralytics often given for intubation mask motor symptoms of generalized convulsive SE, and once paralysis has occurred, treatment decisions should be made with the assumption that the patient is very likely still seizing electrographically. Reviews of treatment for refractory SE are myriad50; however, available high-level evidence is currently limited to one randomized controlled trial that compared propofol and thiopental in a heterogeneous group of patients with refractory SE.51 Questions remain regarding optimal approaches to treatment, and available evidence does not support any preference between midazolam, propofol, and pentobarbital.52 Use of these medications, particularly if paralytics have been used for intubation, requires continuous EEG monitoring to guide therapy.
In patients with suspected nonconvulsive SE, the decision to intubate and/or begin anesthetic medications in the ED is complicated and requires consideration of underlying etiology, the risks of aggressive treatment, and the efficacy of nonaggressive treatment.53 Similarly difficult situations include elderly patients with do-not-resuscitate/intubate orders and patients with focal motor SE and a preserved level of consciousness. In both of these groups, further treatment with second-line non-anesthetic agents (or even oral administration of AEDs) while avoiding associated hypotension or respiratory failure is preferred. Early consultation with a neurologist experienced in treating SE is required, and all patients with refractory SE or nonconvulsive SE should be admitted to an ICU for initiation of continuous EEG monitoring (or promptly transferred to an EEG-capable center).9
Patients with seizures and SE are commonly encountered in the ED. As a frontline provider, emergency physicians play a crucial role in the management of these patients. Most seizure patients present in noncritical condition following isolated seizures; in these patients, cautious management and avoidance of overly aggressive treatment can minimize complications, such as medication toxicity and sedation. A minority of patients will present in SE, and in these patients, early and aggressive protocol-based treatment is critical to terminating seizures and improving overall outcome.
LITERATURE TABLE
CI, confidence interval; OR, odds ratio.
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